{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T15:49:19Z","timestamp":1779896959178,"version":"3.53.1"},"reference-count":52,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2016,7,11]],"date-time":"2016-07-11T00:00:00Z","timestamp":1468195200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>The environmental factors that lead to the reactivation of human T cell leukemia virus type-1 (HTLV-I) in latently infected T cells in vivo remain unknown. It has been previously shown that heat shock (HS) is a potent inducer of HTLV-I viral protein expression in long-term cultured cell lines. However, the precise HTLV-I protein(s) and mechanisms by which HS induces its effect remain ill-defined. We initiated these studies by first monitoring the levels of the trans-activator (Tax) protein induced by exposure of the HTLV-I infected cell line to HS. HS treatment at 43 \u00b0C for 30 min for 24 h led to marked increases in the level of Tax antigen expression in all HTLV-I-infected T cell lines tested including a number of HTLV-I-naturally infected T cell lines. HS also increased the expression of functional HTLV-I envelope gp46 antigen, as shown by increased syncytium formation activity. Interestingly, the enhancing effect of HS was partially inhibited by the addition of the heat shock protein 70 (HSP70)-inhibitor pifithlin-\u03bc (PFT). In contrast, the HSP 70-inducer zerumbone (ZER) enhanced Tax expression in the absence of HS. These data suggest that HSP 70 is at least partially involved in HS-mediated stimulation of Tax expression. As expected, HS resulted in enhanced expression of the Tax-inducible host antigens, such as CD83 and OX40. Finally, we confirmed that HS enhanced the levels of Tax and gp46 antigen expression in primary human CD4+ T cells isolated from HTLV-I-infected humanized NOD\/SCID\/\u03b3c null (NOG) mice and HTLV-I carriers. In summary, the data presented herein indicate that HS is one of the environmental factors involved in the reactivation of HTLV-I in vivo via enhanced Tax expression, which may favor HTLV-I expansion in vivo.<\/jats:p>","DOI":"10.3390\/v8070191","type":"journal-article","created":{"date-parts":[[2016,7,11]],"date-time":"2016-07-11T09:47:19Z","timestamp":1468230439000},"page":"191","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Heat Shock Enhances the Expression of the Human T Cell Leukemia Virus Type-I (HTLV-I) Trans-Activator (Tax) Antigen in Human HTLV-I Infected Primary and Cultured T Cells"],"prefix":"10.3390","volume":"8","author":[{"given":"Marie","family":"Kunihiro","sequence":"first","affiliation":[{"name":"Department of Immunology, Graduate School of Medicine, University of the Ryukyus, Okinawa, 903-0215, Japan"},{"name":"EM Research Organization Inc., Okinawa, 901-2311, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideki","family":"Fujii","sequence":"additional","affiliation":[{"name":"Department of Immunology, Graduate School of Medicine, University of the Ryukyus, Okinawa, 903-0215, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuya","family":"Miyagi","sequence":"additional","affiliation":[{"name":"Department of Immunology, Graduate School of Medicine, University of the Ryukyus, Okinawa, 903-0215, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiaki","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Immunology, Graduate School of Medicine, University of the Ryukyus, Okinawa, 903-0215, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reiko","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Immunology, Graduate School of Medicine, University of the Ryukyus, Okinawa, 903-0215, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuya","family":"Fukushima","sequence":"additional","affiliation":[{"name":"Laboratory of Hematoimmunology, School of Health Sciences, Faculty of Medicine, University of the Ryukyus, Okinawa, 903-0215, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aftab","family":"Ansari","sequence":"additional","affiliation":[{"name":"Department of Pathology, Emory University School of Medicine, Atlanta, GA, 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuetsu","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Immunology, Graduate School of Medicine, University of the Ryukyus, Okinawa, 903-0215, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2016,7,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6476","DOI":"10.1073\/pnas.78.10.6476","article-title":"Adult T-cell leukemia: Antigen in an ATL cell line and detection of antibodies to the antigen in human sera","volume":"78","author":"Hinuma","year":"1981","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1038\/294268a0","article-title":"Isolation of a new type C retrovirus (HTLV) in primary uncultured cells of a patient with sezary T-cell leukaemia","volume":"294","author":"Poiesz","year":"1981","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1038\/331540a0","article-title":"Isolation of an HTLV-1-like retrovirus from patients with tropical spastic paraparesis","volume":"331","author":"Jacobson","year":"1988","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"388","DOI":"10.3389\/fmicb.2012.00388","article-title":"Epidemiological Aspects and World Distribution of HTLV-1 Infection","volume":"3","author":"Gessain","year":"2012","journal-title":"Front. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1007\/s12185-011-0934-4","article-title":"Current status of HTLV-1 infection","volume":"94","author":"Watanabe","year":"2011","journal-title":"Int. J. Hematol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1002\/(SICI)1097-0215(20000201)85:3<319::AID-IJC4>3.0.CO;2-B","article-title":"Evaluation of adult T-cell leukemia\/lymphoma incidence and its impact on non-Hodgkin lymphoma incidence in southwestern Japan","volume":"85","author":"Arisawa","year":"2000","journal-title":"Int. J. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1182\/blood-2009-12-257410","article-title":"Human T-cell leukemia virus type I (HTLV-1) proviral load and disease progression in asymptomatic HTLV-1 carriers: A nationwide prospective study in japan","volume":"116","author":"Iwanaga","year":"2010","journal-title":"Blood"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1002\/ijc.20737","article-title":"Potential immunogenicity of adult T cell leukemia cells in vivo","volume":"114","author":"Kurihara","year":"2005","journal-title":"Int. J. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4231","DOI":"10.4049\/jimmunol.166.6.4231","article-title":"A milk protein lactoferrin enhances human T cell leukemia virus type I and suppresses HIV-1 infection","volume":"166","author":"Moriuchi","year":"2001","journal-title":"J. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1128\/JVI.75.1.192-198.2001","article-title":"Reciprocal interactions between human t-lymphotropic virus type 1 and prostaglandins: Implications for viral transmission","volume":"75","author":"Moriuchi","year":"2001","journal-title":"J. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1006\/viro.1997.8636","article-title":"Signaling via the CD2 receptor enhances HTLV-1 replication in T lymphocytes","volume":"234","author":"Guyot","year":"1997","journal-title":"Virology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6264","DOI":"10.1128\/JVI.72.7.6264-6270.1998","article-title":"Activation of human T-cell leukemia virus type 1 TAX gene expression in chronically infected T cells","volume":"72","author":"Lin","year":"1998","journal-title":"J. Virol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.virol.2005.05.015","article-title":"Activation of human T cell leukemia virus type 1 LTR promoter and cellular promoter elements by T cell receptor signaling and HTLV-1 TAX expression","volume":"339","author":"Lin","year":"2005","journal-title":"Virology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1006\/viro.1995.1218","article-title":"Enhanced human T-cell lymphotropic virus type-1 expression following induction of the cellular stress-response","volume":"208","author":"Andrews","year":"1995","journal-title":"Virology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6657","DOI":"10.1128\/JVI.02270-05","article-title":"Genotoxic stress and cellular stress alter the subcellular distribution of human T-cell leukemia virus type 1 TAX through a CRM1-dependent mechanism","volume":"80","author":"Gatza","year":"2006","journal-title":"J. Virol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"646","DOI":"10.3390\/cells1030646","article-title":"Virus-heat shock protein interaction and a novel axis for innate antiviral immunity","volume":"1","author":"Kim","year":"2012","journal-title":"Cells"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/jidsymp.2009.7","article-title":"Effects of infrared radiation and heat on human skin aging in vivo","volume":"14","author":"Cho","year":"2009","journal-title":"J. Investig. Dermatol. Symp. Proc."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/s12977-015-0185-1","article-title":"Human T-cell leukemia virus type-1 TAX induces the expression of CD83 on T cells","volume":"12","author":"Tanaka","year":"2015","journal-title":"Retrovirology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"13640","DOI":"10.1128\/JVI.02006-13","article-title":"HSP90 protects the human T-cell leukemia virus type 1 (HTLV-1) tax oncoprotein from proteasomal degradation to support NF-kappa B activation and HTLV-1 replication","volume":"87","author":"Gao","year":"2013","journal-title":"J. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1771","DOI":"10.1016\/S0960-9822(01)00540-1","article-title":"Human T cell leukemia virus type 1 TAX associates with a molecular chaperone complex containing HTID-1 and HSP70","volume":"11","author":"Cheng","year":"2001","journal-title":"Curr. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"354","DOI":"10.4049\/jimmunol.147.1.354","article-title":"Identification of a neutralization epitope on the envelope gp46 antigen of human T cell leukemia virus type I and induction of neutralizing antibody by peptide immunization","volume":"147","author":"Tanaka","year":"1991","journal-title":"J. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1089\/aid.2007.0092","article-title":"Enhancement of OX40-induced apoptosis by TNF coactivation in OX40-expressing T cell lines in vitro leading to decreased targets for HIV type 1 production","volume":"24","author":"Takahashi","year":"2008","journal-title":"AIDS Res. Hum. Retrovir."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"6748","DOI":"10.1128\/JVI.75.15.6748-6757.2001","article-title":"OX40 stimulation by gp34\/OX40 ligand enhances productive human immunodeficiency virus type 1 infection","volume":"75","author":"Takahashi","year":"2001","journal-title":"J. Virol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Ohnishi, K., Ohkura, S., Nakahata, E., Ishisaka, A., Kawai, Y., Terao, J., Mori, T., Ishii, T., Nakayama, T., and Kioka, N. (2013). Non-specific protein modifications by a phytochemical induce heat shock response for self-defense. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0058641"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.canlet.2012.06.003","article-title":"Inhibition of HSP70: A challenging anti-cancer strategy","volume":"325","author":"Goloudina","year":"2012","journal-title":"Cancer Lett."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1089\/aid.2013.0214","article-title":"Elimination of Human T cell Leukemia Virus Type-1-Infected Cells by Neutralizing and Antibody-Dependent Cellular Cytotoxicity-Inducing Antibodies Against Human T cell Leukemia Virus Type-1 Envelope gp46","volume":"30","author":"Tanaka","year":"2014","journal-title":"AIDS Res. Hum. Retrovir."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1002\/ijc.2910480423","article-title":"Production of a recombinant human T-cell leukemia virus type-1 trans-activator (TAX1) antigen and its utilization for generation of monoclonal antibodies against various epitopes on the TAX1 antigen","volume":"48","author":"Tanaka","year":"1991","journal-title":"Int. J. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1089\/aid.1992.8.227","article-title":"An antigenic structure of the trans-activator protein encoded by human T-cell leukemia virus type-1 (HTLV-1), as defined by a panel of monoclonal antibodies","volume":"8","author":"Tanaka","year":"1992","journal-title":"AIDS Res. Hum. Retrovir."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1002\/ijc.2910360506","article-title":"A glycoprotein antigen detected with new monoclonal antibodies on the surface of human lymphocytes infected with human T-cell leukemia virus type-1 (HTLV-1)","volume":"36","author":"Tanaka","year":"1985","journal-title":"Int. J. Cancer"},{"key":"ref_30","first-page":"74","article-title":"The neutralizing function of the anti-HTLV-1 antibody is essential in preventing in vivo transmission of HTLV-1 to human T cells in NOD-SCID\/\u03b3cnull (NOG) mice","volume":"11","author":"Saito","year":"2014","journal-title":"Retrovirology"},{"key":"ref_31","unstructured":"Kunihiro, M., and Tanaka, Y. Transient upregulation of Tax and gp46 by heat shock. Unpublished."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1128\/jvi.71.1.741-745.1997","article-title":"The cellular stress response enhances human T-cell lymphotropic virus type 1 basal gene expression through the core promotor region of the long terminal repeat","volume":"71","author":"Andrews","year":"1997","journal-title":"J. Virol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2905","DOI":"10.1099\/0022-1317-79-12-2905","article-title":"The effect of the cellular stress response on human T-lymphotropic virus type I envelope protein expression","volume":"79","author":"Andrews","year":"1998","journal-title":"J. Gen. Virol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.bbrc.2015.11.113","article-title":"CREB is activated by ER stress and modulates the unfolded protein response by regulating the expression of IRE1\u03b1 and PERK","volume":"469","author":"Kikuchi","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Li, L., Tan, H., Gu, Z., Liu, Z., Geng, Y., Liu, Y., Tong, H., Tang, Y., Qiu, J., and Su, L. (2014). Heat stress induces apoptosis through a Ca2+-mediated mitochondrial apoptotic pathway in human umbilical vein endothelial cells. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0111083"},{"key":"ref_36","first-page":"2504","article-title":"c-Myc and c-Myb protein degradation: Effect of metabolic inhibitors and heat shock","volume":"8","author":"Luscher","year":"1988","journal-title":"Mol. Cell. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6035","DOI":"10.1038\/sj.onc.1208970","article-title":"Cellular immune response to HTLV-1","volume":"24","author":"Bangham","year":"2005","journal-title":"Oncogene"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1532\/IJH97.07092","article-title":"Immunologic control of human T-cell leukemia virus type I and adult T-cell leukemia","volume":"86","author":"Kannagi","year":"2007","journal-title":"Int. J. Hematol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1007\/s12192-012-0348-0","article-title":"Heat shock enhances the expression of cytotoxic granule proteins and augments the activities of tumor-associated antigen-specific cytotoxic t lymphocytes","volume":"17","author":"Takahashi","year":"2012","journal-title":"Cell Stress Chaperones"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1080\/02656730701822087","article-title":"Heat shock suppresses human NK cell cytotoxicity via regulation of perforin","volume":"13","author":"Harada","year":"2007","journal-title":"Int. J. Hyperth."},{"key":"ref_41","unstructured":"Kunihiro, M., and Tanaka, Y. Heat shock inactivated ADCC activity of PBMC to HTLV-I infected cells. (unpublished; manuscript in preparation)."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2102","DOI":"10.1182\/blood.V94.6.2102","article-title":"Arsenic trioxide selectively induces acute promyelocytic leukemia cell apoptosis via a hydrogen peroxide-dependent pathway","volume":"94","author":"Jing","year":"1999","journal-title":"Blood"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1248\/bpb.32.1286","article-title":"Arsenic trioxide inhibits human T cell-lymphotropic virus-1-induced syncytiums by down-regulating gp46","volume":"32","author":"Nabeshi","year":"2009","journal-title":"Biol. Pharma. Bull."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1007\/s12192-011-0262-x","article-title":"Theiler's murine encephalomyelitis virus infection induces a redistribution of heat shock proteins 70 and 90 in BHK-21 cells, and is inhibited by novobiocin and geldanamycin","volume":"16","author":"Mutsvunguma","year":"2011","journal-title":"Cell Stress Chaperones"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.virol.2014.02.016","article-title":"The ns5a-binding heat shock proteins HSC70 and HSP70 play distinct roles in the hepatitis c viral life cycle","volume":"454\u2013455","author":"Khachatoorian","year":"2014","journal-title":"Virology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.virol.2015.02.014","article-title":"Heat shock protein 70 is associated with CSFV NS5A protein and enhances viral rna replication","volume":"482","author":"Zhang","year":"2015","journal-title":"Virology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1128\/jvi.66.2.1040-1049.1992","article-title":"Complex formation of human T-cell leukemia virus type I p40tax transactivator with cellular polypeptides","volume":"66","author":"Nagata","year":"1992","journal-title":"J. Virol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1006\/bbrc.1999.1028","article-title":"Heat shock cognate protein 70 is a cell fusion-enhancing factor but not an entry factor for human T-cell lymphotropic virus type I","volume":"261","author":"Fang","year":"1999","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1002\/ijc.22403","article-title":"Inhibition of heat shock protein-90 modulates multiple functions required for survival of human T-cell leukemia virus type I-infected T-cell lines and adult T-cell leukemia cells","volume":"120","author":"Kawakami","year":"2007","journal-title":"Int. J. Cancer"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"768","DOI":"10.3390\/toxins4100768","article-title":"Antibody to heat shock protein 70 (HSP70) inhibits human T-cell lymphoptropic virus type I (HTLV-I) production by transformed rabbit T-cell lines","volume":"4","author":"Fallouh","year":"2012","journal-title":"Toxins"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.jphotobiol.2015.12.014","article-title":"Infrared and skin: Friend or foe","volume":"155","author":"Barolet","year":"2016","journal-title":"J. Photochem. Photobiol. B"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e1002792","DOI":"10.1371\/journal.ppat.1002792","article-title":"Hyperthermia Stimulates HIV-1 Replication","volume":"8","author":"Roesch","year":"2012","journal-title":"PLoS Pathog."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/8\/7\/191\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T19:25:50Z","timestamp":1760210750000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/8\/7\/191"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,7,11]]},"references-count":52,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2016,7]]}},"alternative-id":["v8070191"],"URL":"https:\/\/doi.org\/10.3390\/v8070191","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,7,11]]}}}